Cancer can be defined as an abnormal growth of tissues characterized by a loss of cellular differentiation.
The phosphatidylinositol-3-kinase (PI3K) pathway plays an important role in cellular signaling. Phosphatidylinositol-3-kinases or phosphoinositol-3-kinases (PI3-kinases or PI3 Ks) are a family of related enzymes that are capable of phosphorylating the 3 position hydroxyl group of the inositol ring of phosphatidylinositol. The PI3K family is composed of Class I, II and Class III. The classification is based on primary structure, regulation and in vitro lipid substrate specificity. Class III PI3K enzymes phosphorylate PI alone while, Class II PI3K enzymes phosphorylate both PI and PI 4-phosphate [PI(4)P].
Class I PI3K enzymes phosphorylate PI, PI(4)P and PI 4,5-biphosphate[PI(4,5)P2]. Class I PI3Ks are further divided into two groups, class Ia and class Ib, in terms of their activation mechanism. Class Ia PI3Ks include PI3K p110α, p110β and p110δ subtypes and are generally activated in response to growth factor-stimulation of receptor tyrosine kinases. The first two p110 isoforms (α and β) are expressed in all cells, but p110δ is primarily expressed in leukocytes. Class Ib enzymes consist of p110γ catalytic subunit that interacts with a p110 regulatory subunit. It is activated in response to G-protein coupled receptor systems and its expression appears to be limited to leukocytes and cardiomyocytes. Class Ia subtypes are considered to be associated with cell proliferation and carcinogenesis.
mTOR is a class IV PI-3 kinase family member with protein kinase activity, but lacks any lipid kinase activity. It regulates cell growth and metabolism in response to environmental cue hence inhibitors of mTOR may be useful in the treatment of cancer and metabolic disorders (Cell, 2006, 124, 471-484).
PI3K mediated signaling pathway plays a very important role in cancer cell survival, cell proliferation, angiogenesis and metastasis. The PI3K pathway is activated by stimuli such as growth factors, hormones, cytokines, chemokines and hypoxic stress. Activation of PI3K results in the recruitment and activation of protein kinase B (AKT) to the membrane, which gets phosphorylated at Serine 473 (Ser-473). Thus, phosphorylation of Ser-473 of AKT is a read-out/detector for the activation of the PI3K-mediated pathway. A cell-based ELISA technique can be used to study such activation.
AKT is known to positively regulate cell growth (accumulation of cell mass) by activating the mTOR serine threonine kinase. mTOR serves as a molecular sensor that regulates protein synthesis on the basis of nutrients. mTOR regulates biogenesis by phosphorylating and activating p70S6 kinase (S6K1), which in turn enhances translation of mRNAs that have polypyrimidine tracts. The phosphorylation status of S6K1 is a bonafide read-out of mTOR function.
Most tumors have an aberrant PI3K pathway (Nat. Rev. Drug Discov., 2005, 4, 988-1004). Since mTOR lies immediately downstream of PI3K, these tumors also have hyperactive mTOR function. Thus, most of the cancer types can be treated using the molecules that target PI3K and mTOR pathways.
The compounds that are PI3K and/or mTOR and/or STAT3 inhibitors, find use in the treatment of cancers. Compounds are used to reduce, inhibit, or diminish the proliferation of tumor cells, and thereby assist in reducing the size of a tumor.
Signal transducer and activator of transcription 3 also known as STAT3 is a transcription factor which in humans is encoded by the STAT3 gene. The protein encoded by this gene is a member of the STAT protein family. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and apoptosis. Constitutive STAT3 activation is associated with various human cancers and commonly suggests poor prognosis. It has anti-apoptotic as well as proliferative effects.
The compounds that are STAT3 inhibitors, find use in the treatment of cancers. These compounds are used to reduce, inhibit, or diminish the proliferation of tumor cells.
SF 1126 (Semaphore, Inc.) is a pan-PI3K inhibitor in phase I clinical trials. SF1126 is a covalent conjugate of LY294002 containing a peptide-based targeting group.
GDC-0941 (Piramed Ltd. and Genentech, Inc.) is a PI3K inhibitor and is in phase I clinical trials.
BEZ-235 (Novartis AG), which is currently in phase I/II clinical trials, inhibits all isoforms of PI3K and also inhibits the kinase activity of mTOR.
XL-765 (Exelixis Inc.) is also a dual inhibitor of mTOR and PI3K. The compound is in phase I clinical trials as an oral treatment for solid tumors.
PIK-75 (Astellas Pharma Inc.) is in preclinical studies. It is a PI3Kalpha inhibitor and inhibits p110α>200 fold more than plifβ.
Inflammation is the response of a tissue to injury that may be caused by a biological assault such as invading organisms and parasites, ischemia, antigen-antibody reactions or other forms of physical or chemical injury. It is characterized by increased blood flow to the tissue, causing pyrexia, erythema, induration and pain.
Several proinflammatory cytokines, especially TNF-α and interleukins (IL-1β, IL-6, IL-8) play an important role in the inflammatory process. Both IL-1 and TNF-α are derived from mononuclear cells and macrophages and in turn induce the expression of a variety of genes that contribute to the inflammatory process. An increase in TNF-α synthesis/release is a common phenomenon during the inflammatory process. Inflammation is an inherent part of various disease states like rheumatoid arthritis, Crohn's disease, ulcerative colitis, septic shock syndrome, psoriasis, atherosclerosis, among other clinical conditions.
The first line of treatment for inflammatory disorders involves the use of non-steroidal anti-inflammatory drugs (NSAIDs) e.g. ibuprofen, naproxen to alleviate symptoms such as pain. However, despite the widespread use of NSAIDs, many individuals cannot tolerate the doses necessary to treat the disorder over a prolonged period of time as NSAIDs are known to cause gastric erosions. Moreover, NSAIDs merely treat the symptoms of disorder and not the cause. When patients fail to respond to NSAIDs, other drugs such as methotrexate, gold salts, D-penicillamine and corticosteroids are used. These drugs also have significant toxic effects.
Monoclonal antibody drugs such as Infliximab, Etanercept and Adalimumab are useful as anti-inflammatory agents, but have drawbacks such as route of administration (only parenteral), high cost, allergy induction, activation of latent tuberculosis, increased risk of cancer and congestive heart disease.
PI3K inhibitors are known in the art. For example, U.S. Pat. No. 6,403,588 describes phosphatidylinositol 3 kinase inhibitors useful as antitumor agents. Additionally, WO 2004/017950 describes phosphatidylinositol 3,5-biphosphate inhibitors as anti-viral agents.